The present application concerns inhibitors of matrix metalloproteases. In particular it concerns 3-aryl-succinamido-hydroxamic acids.
In healthy tissue there is an equilibrium between synthesis and degradation of the extracellular matrix. The extracellular matrix is mainly degraded by proteases of the matrix metalloprotease (MMP) family. Examples of members of this family are collagenases, stromelysins and gelatinases. In healthy tissue this degradation is regulated by inhibition with TIMPs (tissue inhibitor of metalloproteases). This equilibrium between matrix metalloproteases and TIMPs is disturbed in various diseases such as rheumatoid and osteoarthritis, multiple sclerosis, metastasis and invasion of tumours, cornea ulcer, meningitis, cardiovascular diseases such as restenosis and arteriosclerosis as well as diseases of bones and gums. Many examples show that an inhibition of these enzymes can have a positive influence on the clinical picture of these diseases (Beckett et al., 1996).
The two gelatinases A (MMP-2) and B (MMP-9) appear to be the most important MMPs for metastasis and invasion. A selective inhibition of these two enzymes would be desirable. The furthest developed substance at present in this area, Marimastat, which is in clinical phase III is active but exhibits major side-effects such as muscle pain. In its present form Marimastat is a broad-range MMP inhibitor and consequently MMPs like MMP1 which are absolutely essential for tissue metabolism are also inhibited. It is generally assumed that the side-effects are due to the non-specificity.
It has now surprisingly been found that the new 3-aryl-succinamido-propionohydroxamic acids have a more favourable pharmacological profile than Marimastat. These substances differ inter alia from Marimastat by an aryl substitution at position 3 of the succinyl residue. The specificity with respect to gelatinases is considerably improved in the new compounds or rather is now present for the first time. I.e. it is possible to avoid inhibition of MMP1 and other important enzymes.
The present application concerns substances of the general formula I 
In order to achieve an optimal inhibition of the gelatinases, the residues R and R1 of the compounds of the general formula I should have certain hydrophobicities. A suitable parameter for this is clogP which can be determined with the aid of xe2x80x9cPCModels clogp3xe2x80x9d from Daylight Chemical Information Systems Inc. (1993). The coefficients are based on Hansch, C. and Leo, A.: Substituent Constants for Correlation Analysis in Chemistry and Biology. Wiley Interscience New York (1979), whereas the algorithm is based on the following citation: Chou, J. and Jurs, P., J. Chem. Inf. Comput. Sci. 19, 172 (1979). The fragments are entered as complete molecules for the calculation i.e. not as a radical or ion. In order to get informative values the clogP values for R are determined together with the neighbouring phenyl ring (Ph-R fragments). The clogP values for the residue R1 are determined together with the neighbouring carbonyl and amino group as (CHO)(NH2)CHR1 (aminocarbonyl-R1 fragments).
Examples for Ph-R 
Examples for aminocarbonyl-R1: 
The clogP values for R in the form of Ph-R fragments in the compounds of the present invention are 2.0 to 6.0, preferably 2.5 to 5.0, particularly preferably 3.0 to 4.5.
The clogP values for R1 in the form of aminocarbonyl-R1 fragments in the compounds of the present invention are between xe2x88x921.5 and 2.0, preferably between xe2x88x921.2 and 1.5, particularly preferably between xe2x88x921.0 and 1.2.
The present application therefore concerns substances of the general formula I 
in which
R as a Ph-R fragment has a clogP value between 2.0 and 6.0, preferably between 2.5 and 5.0 and particularly preferably between 3.0 and 4.5,
R1 as an aminocarbonyl-R1 fragment has a clogP value between xe2x88x921.5 and 2.0, preferably between xe2x88x921.2 and 1.5 and particularly preferably between xe2x88x921.0 and 1.2 and
R5 denotes hydrogen or a C1-C8 alkyl residue
R6 denotes hydrogen, an optionally substituted C1-C8 alkyl or an optionally substituted monocyclic or bicyclic cycloalkyl, aryl, heteroaryl, aralkyl or alkylheteroaryl residue, or
R5 and R6 together with the N atom denote a saturated or unsaturated 5-membered or 6-membered ring which contains at most one additional heteroatom,
pharmacologically compatible salts, esters and derivatives thereof which are metabolized in vivo into compounds of the general formula I as well as the use of these compounds for the production of pharmaceutical preparations.
Alternatively the subject matter of the present application can be represented as compounds of the general formula I: 
in which
R denotes an optionally substituted C1-C8 alkyl, or an optionally substituted monocyclic or bicyclic cycloalkyl, aryl, heteroaryl, aryloxy, heteroaryloxy, or aralkyl residue,
R1 denotes an optionally substituted C1-C8 alkyl or an optionally substituted monocyclic or bicyclic cycloalkyl, aryl, heteroaryl, aralkyl or alkylheteroaryl residue,
R5 denotes hydrogen or a C1-C8 alkyl residue
R6 denotes hydrogen, an optionally substituted C1-C8 alkyl or an optionally substituted monocyclic or bicyclic cycloalkyl, aryl, heteroaryl, aralkyl or alkylheteroaryl residue, or
R5 and R6 together with the N atom denote a saturated or unsaturated 5-membered or 6-membered ring which contains at most one additional heteroatom,
pharmacologically compatible salts, esters and derivatives thereof which are metabolized in vivo into compounds of the general formula I as well as the use of these compounds for the production of pharmaceutical preparations.
The residues listed under R, R1 and R6 can, independently of one another, be optionally substituted once, twice or three times by halogen, hydroxy, thio, alkyl, C3-C8 cycloalkyl, C4-C8 cycloalkenyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, chloroalkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, amino, alkylamino, dialkylamino, nitro, carboxyl, carboxamido, alkoxycarbonyl, alkoxycarbonylalkyl, perfluoroalkyl or amino or aminocarbonyl optionally substituted once or twice by lower alkyl, nitrile, oxo or acyl.
In this connection a halogen, hydroxy, oxo, thio, alkoxy, xcfx89-hydroxyalkoxy, xcfx89-chloroalkoxy, alkylthio, amino, aminocarbonyl, carboxyl and acyl group are preferred. Methyl, halogen and hydroxyl are particularly preferred.
If they are substituted a single substitution is preferred.
If not stated otherwise cycloalkyl denotes a saturated mono or polyunsaturated carbocycle or heterocycle containing 3 to 8 structural atoms, preferably 5-7 structural atoms which can optionally be interrupted once or several times by heteroatoms such as nitrogen, oxygen or sulphur and in particular denotes a cyclopentyl, cyclohexyl, cycloheptyl, morpholinyl, thiamorpholinyl, piperidinyl, piperazinyl, tetrahydrofuryl or tetrahydropyranyl residue.
The alkyl residue in aralkyl and heteroalkyl in R, R1 and R6 denotes independently of one another C1 or C2 alkyl.
Acyl in the residues R, R1 and R6 denotes above all the acetyl group.
If not stated otherwise in the residues R, R1 and R6 alkyl alone or in combination e.g. with alkoxy, alkylthio, arylsulfonyl, alkylsulfonyl, alkylamino-carbonyl, arylaminocarbonyl, alkylamino, alkoxycarbonyl, aryloxycarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, denotes a straight-chained or branched, saturated or unsaturated residue with 1-3 carbon atoms such as methyl, ethyl, propyl, isopropyl, allyl or propinyl.
C1-C8 alkyl in the residues R, R1, R5 and R6 denotes independently of one another a straight-chained, branched, saturated or unsaturated residue containing 1 to 8 carbon atoms which can be interrupted by 1 or 2 heteroatoms such as O, N or S, where no interruption or an interruption by oxygen is preferred and in the case of an interruption by oxygen C1-C7 alkoxy is particularly preferred. Examples of C1-C8 alkyl residues are methyl, ethyl, propyl, pentyl, octyl, allyl, propargyl, 2,4-pentadienyl, isopropyl, sec.butyl, tert.butyl, 3-methyl-butyl, 2-hydroxy-hexyl, n-butoxy, hexyloxy, C(CH3)2)OMe in particular tert. butyl, n-butoxy, hexyloxy, C(CM3)2oMe.
Aryl is understood as a phenyl or naphthyl residue which can be optionally substituted especially by halogen, alkyl or alkoxy. A phenyl residue is preferred.
Halogen is understood as chlorine, bromine or iodine, preferably chlorine.
Structural atoms are understood as C, N, O and S and heteroatoms are understood as N, O and S.
The heteroaryl residues listed for R, R1 and R6 denote independently of one another a pyridine, pyrimidine, pyridazine, pyrazine, piperazine, imidazole, furan, oxazole, isothiazole, isooxazole, 1,2,3-triazole or 1,2,4-triazole, thiazole, thiophene or indole ring, preferably a pyridine, imidazole or thiophene ring.
The bicycles listed under R, R1 and R6 are preferably residues such as naphthyl, tetrahydronaphthyl, dekalinyl, quinolyl, isoquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, benzimidazolyl, indazolyl, oxindolyl, benzofuranyl, benzothienyl, benzthiazolyl, benzoxazolyl or a purinyl residue, in particular a naphthyl, quinolyl, isoquinolyl, tetrahydroquinolyl, indolyl or benzimidazolyl residue.
Preferred residues for R are 4 to 7 structural atoms for alkyl and cycloalkyl, and 5 to 10 and particularly preferably 6 to 8 structural atoms are preferred for aryl, bicyclic and heteroaryl residues.
Preferred residues for R1 are 1 to 12 structural atoms particularly preferably 3 to 10 structural atoms.
Especially preferred residues for R are: xe2x80x94O-phenyl(p-R2), phenyl(p-R2), n-butoxy, hexyloxy in which R2 represents a small substituent such as hydrogen, halogen, methyl or hydroxyl; especially preferred residues for R are xe2x80x94O-phenyl, phenyl and n-butoxy.
Especially preferred residues for R1 are the residues benzyl, phenyl, tert.butyl or C(CH3)2OMe and in particular tert.butyl.
Preferred residues for R5 are hydrogen, methyl and ethyl; hydrogen is particularly preferred.
Preferred residue for R6 are methyl and ethyl, phenyl and pyridyl; methyl is particularly preferred.
If R5 and R6 form a ring this preferably contains oxygen and is particularly preferably morpholino.
The invention in addition concerns all optical isomers and racemates. The following optical isomers are preferred: C2 of the succinylhydroxamic acid and Cxcex1 of the amino-acid amide in the S configuration and C3 of the succinic acid parent substance in the R configuration. 
The compounds of the invention of the general formula I can be synthesized by known processes. The optical isomers can be separated by known methods. Whenever appropriate the described processes relate to the separation of final products and/or precursors. The diasteromeric salts are either formed from the racemic mixtures by reaction with an optically active acid such as D- or L-tartaric acid, mandelic acid, malic acid, lactic acid or camphorsulfonic acid or with an optically active amine such as D- or L-xcex1-phenylethyl-amine, ephedrine, quinidine or cinquonidine which can be separated by crystallization, or the optical isomers are separated by HPLC. Another method of separating optical isomers is an enzymatic separation during synthesis and/or synthesis of intermediate products.
The compounds of the general formula I are obtainable by
(a) Reacting a carboxylic acid of the general formula II in which R, R1, R5 and R6 have the above-mentioned meanings and in which the alcoholic hydroxy group can be present free or protected for example by ester formation with acetic acid, 
xe2x80x83with hydroxylamine or with an O-protected or N,O-protected hydroxylamine and subsequently cleaving the protecting group.
For these reactions carboxylic acids can be activated by methods known from peptide chemistry. For example carboxylic acids can be activated directly by reaction with chloroformic esters, carbodiimides, N,Nxe2x80x2-carbonyl-diimidazole, 2-chloro-N-methylpyridinium iodide or an intermediate reaction can be carried out to form active esters such as pentafluorophenyl, N-hydroxysuccinimide, N-hydroxybenzotriazole esters which can then be reacted with hydroxylamine or a protected hydroxylamine. After completion of the reaction of a protected hydroxylamine derivative, the protecting groups are cleaved off by known methods. Examples of protected hydroxylamines are O-benzylhydroxylamine, O-p-methoxybenzylhydroxylamine, O-trimethylsilylhydroxylamine, and O-tert-butyl-hydroxylamine, N,O-dibenzylhydroxylamine and N,O-bis-p-methoxybenzyl-hydroxylamine. The protecting groups can be cleaved in the case of benzyl or p-methoxybenzyl groups by hydrogenolysis or in the latter case or in the case of the O-tert-butyl group also by acid hydrolysis. A trimethylsilyl protecting group can be hydrolysed by water.
(b) As an alternative to (a), the compounds of formula I can be prepared by reacting a 1,3-dioxolan-4-one of the general formula III in which R3 and R4 represent hydrogen, lower alkyl or phenyl and preferably methyl with hydroxylamine. 
The compounds of the general structure II can be prepared by alkaline hydrolysis from compounds of the structure III.
Compounds of the general structure III are obtainable by coupling a 2-aryl-3-hydroxy-succinic acid of the general structure IVa in which R, R3 and R4 have the aforementioned meaning and whose hydroxy group and the neighbouring COOH group are protected with formation of a 1,3-dioxolan-4-one structure, 
with racemic or optically homogeneous xcex1 amino acids e.g. (R) or (S)-tert-butyl-glycine-N-methylamide by methods which are known from peptide chemistry. For example active esters such as N-hydroxysuccinimide, 1-hydroxybenzotriazole or pentafluorophenyl esters can be prepared by activating the COOH group in IVa by carbodiimides such as di-cyclohexylcarbodiimide or di-isopropylcarbodiimide which can then react with the free amino group of an xcex1-amino-acid amide substituted on the amide group. These esters can also be prepared without isolation and reacted further. Other methods of activation include the preparation of mixed anhydrides by reacting the carboxylic acids with chloroformic acid esters or condensation reagents such as uronium salts e.g. 2H-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl-uronium-tetrafluoroborate.
The carboxylic acids of formula IVa can be prepared by reacting xcex1-formylarylacetic acids of the general formula V 
in which R has the above-mentioned meaning with alkali cyanides or trimethylsilyl cyanide/zinc iodide, acid saponification of the cyanohydrins of the general structure VI which are obtained as intermediate products and subsequently protecting the hydroxy and the COOH group by an acid catalysed reaction with acetals or ketals e.g. 2,2-dimethoxypropane. The cyanohydrins can also be prepared as optically active molecules by enzymatic reaction of the compound of the general structure V catalysed by (R)- or (S)-oxynitrilases which yield stereospecifically the R or S compound respectively.
Alternatively compounds of formula IVa can be prepared by reducing oxalo-arylacetic esters e.g. with sodium borohydride, acid saponification of the esters and subsequent protection of the hydroxy group and the neighbouring COOH group by an acid catalysed reaction with acetals or ketals e.g. 2,2-dimethoxypropane.
Alkali salts, ammonium salts, acetates or hydrochloride are primarily used as pharmacologically compatible salts which are prepared in the usual manner e.g. by titrating the compounds with inorganic or organic bases or inorganic acids such as e.g. sodium hydroxide, potassium hydroxide, aqueous ammonia, amines such as triethylamine or hydrochloric acid. The salts are usually purified by reprecipitation from water/acetone.
The new substances according to the invention of formula I and salts thereof can be administered enterally or parenterally in a liquid or solid form. All the usual forms of administration come into consideration such as tablets, capsules, dragxc3xa9es, syrups, solutions, suspensions etc. Water is preferably used as an injection medium which contains the usual additives in injection solutions such as stabilizers, solubilizers and buffers.
Such additives are for example tartrate and citrate buffer, ethanol, complexing agents (such as ethylene diamine-tetraacetic acid and non-toxic salts thereof), high molecular polymers (such as liquid polyethylene oxide) to regulate viscosity. Liquid carriers for injection solutions must be sterile and are preferably filled into ampoules. Solid carriers are for example starch, lactose, mannitol, methylcellulose, talcum, highly dispersed silicic acids, higher molecular fatty acids (such as steric acid), gelatine, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats, solid high molecular polymers (such as polyethylene glycols); suitable formulations for oral administration can if desired contain flavouring agents and sweeteners.
The dose can depend on various factors such as manner of administration, species, age and/or individual state. The daily doses to be administered are about 10-1000 mg/person, preferably 100-500 mg/person and can be taken once or divided over several applications.
Apart from the compounds stated in the examples and compounds that can be derived by combining all meanings of the substituents mentioned in the examples, the following 3-aryl-succinamido-hydroxamic acid derivatives are preferred in the sense of the present invention:
1. 2-(biphenyl-4-ylamino)-N1-(2,2-dimethyl-1-methyl-carbamoyl-propyl)-3,N4-dihydroxy-succinamide
2. 2-(biphenyl-4-ylamino)-N1-[2,2-dimethyl-1-(morpholin-4-ylcarbonyl)-propyl]-3,N4-dihydroxy-succinamide
3. 2-(biphenyl-4-ylamino)-N1-[2,2-dimethyl-1-(pyridin-2-ylcarbomoyl)-propyl]-3,N4-dihydroxy-succinamide
4. 2-(biphenyl-4-ylamino)-3,N4-dihydroxy-N1-(1-methyl-carbamoyl-2-phenyl-ethyl)-succinamide
5. N1-(1-benzyl-2-morpholin-4-yl-2-oxo-ethyl)-2-(bipheny-4-ylamino)-3,N4-dihydroxy-succinamide
6. 2-(biphenyl-4-ylamino)-3,N4-dihydroxy-N1-[2-phenyl-1-(pyridin-2-ylcarbamoyl)-ethyl]-succinamide
7. 2-(biphenyl-4-ylamino)-3,N4-dihydroxy-N1-[2-methoxy-2-methyl-1-methylcarbamoyl-propyl]-succinamide
8. 2-(biphenyl-4-ylamino)-3,N4-dihydroxy-N1-[2-methoxy-2-methyl-1-(morpholin-4-carbonyl)-propyl]-succinamide
9. 2-(biphenyl-4-ylamino)-3,N4-dihydroxy-N1-[2-methoxy-2-methyl-1-(pyridin-2-ylcarbamoyl)-propyl]-succinamide
10. N4-(2,2-dimethyl-1-methylcarbamoyl-propyl)-2N1-dihydroxy-3-(4-phenoxy-phenylamino)-succinamide
11. N-4-[2,2-dimethyl-1-(morpholin-4-carbonyl)-propyl]-2,N1-dihydroxy-3-(4-phenoxy-phenylamino)-succinamide
12. N4-[2,2-dimethyl-1-(pyridin-2-ylcarbamoyl)-propyl]-2,N1-dihydroxy-3-(4-phenoxy-phenylamino)-succinamide
13. 2,N1-dihydroxy-N4-(1-methylcarbamoyl-2-phenyl-ethyl)-3-(4-phenoxy-phenylamino)-succinamide
14. N4-(1-benzyl-2-morpholin-4-yl-2-oxo-ethyl)-2,N1-dihydroxy-3-(4-phenoxy-phenylamino)-succinamide
15. 2,N1-dihydroxy-3-(4-phenoxy-phenylamino)-N4-[2-phenyl-1-(pyridin-2-ylcarbamoyl)-ethyl]-succinamide
16. 2,N1-dihydroxy-N4-(2-methoxy-2-methyl-1-methyl-carbamoyl-propyl)-3-(4-phenoxy-phenylamino)-succinamide
17. 2,N1-dihydroxy-N4-[2-methoxy-2-methyl-1-(morpholin-4-carbonyl)-propyl]-3-(4-phenoxy-phenylamino)-succinamide
18. 2,N1-dihydroxy-N4-[2-methoxy-2-methyl-1-(pyridin-2-ylcarbamoyl)-propyl]-3-(4-phenoxy-phenylamino)-succinamide
19. 2-(4-butoxy-phenylamino)-N1-(2,2-dimethyl-1-methyl-carbamoyl-propyl)-3,N4-dihydroxy-succinamide
20. 2-(4-butoxy-phenylamino)-N1-[2,2-dimethyl-1-(morpholin-4-carbonyl)-propyl]-3,N4-dihydroxy-succinamide
21. 2-(4-butoxy-phenylamino)-N1-[2,2-dimethyl-1-(pyridin-2-ylcarbamoyl)-propyl]-3,N4-dihydroxy-succinamide
22. 2-(4-butoxy-phenylamino)-3,N4-dihydroxy-N1-(1-methylcarbamoyl-2-phenyl-ethyl)-succinamide
23. N1-(1-benzyl-2-morpholino-4-yl-2-oxo-ethyl)-2-(4-butoxy-phenylamino)-3,N4-dihydroxy-succinamide
24. 2-(4-butoxy-phenylamino)-3,N4-dihydroxy-N1-[2-phenyl-1-(pyridin-2-ylcarbamoyl)ethyl]-succinamide
25. 2-(4-butoxy-phenylamino)-3,N4-dihydroxy-N1-(2-methoxy-2-methyl-1-methylcarbamoyl-propyl)-succinamide
26. 2-(4-butoxy-phenylamino)-3,N4-dihydroxy-N1-[2-methoxy-2-methyl-1-(morpholin-4-carbonyl)-propyl]-succinamide
27. 2-(4-butoxy-phenylamino)-3,N4-dihydroxy-N1-[2-methoxy-2-methyl-1-(pyridin-2-ylcarbamoyl)-propyl]-succinamide
28. N1-(2,2-dimethyl-1-methylcarbamoyl-propyl)-2-(4-hexyloxy-phenylamino)-3,N4-dihydroxy-succinamide
29. N1-[2,2-dimethyl-1-(morpholin-4-carbonyl)-propyl]-2-(4-hexyloxy-phenylamino)-3N4-dihydroxy-succinamide
30. N1-[2,2-dimethyl-1-(pyridin-2-ylcarbamoyl)-propyl]-2-(4-hexyloxy-phenylamino)-3,N4-dihydroxy-succinamide
31. 2-(4-hexyloxy-phenylamino)-3,N4-dihydroxy-N1-(1-methylcarbamoyl-2-phenyl-ethyl)-succinamide
32. N1-(1-benzyl-2-morpholin-4-yl-2-oxo-ethyl)-2-(4-hexyloxy-phenylamino)-3,N4-dihydroxy-succinamide
33. 2-(4-hexyloxy-phenylamino)-3,N4-dihydroxy-N1-[2-phenyl-1-(pyridin-2-ylcarbamoyl)-ethyl]-succinamide
34. 2-(4-hexyloxy-phenylamino)-3,N4-dihydroxy-N1-(2-methoxy-2-methyl-1-methylcarbamoyl-propyl)-succinamide
35. 2-(4-hexyloxy-phenylamino)-3,N4-dihydroxy-N1-[2-methoxy-2-methyl-1-(morpholin-4-carbonyl)-propyl]-succinamide
36. 2-(4-hexyloxy-phenylamino)-3,N4-dihydroxy-N1-[2-methoxy-2-methyl-1-(pyridin-2-ylcarbamoyl)-propyl]-succinamide